tbuckley/cabot-search huggingface dataset:
EOLP-04. A CALL TO ACTION TO INCREASE ACCESS TO POST-MORTEM BRAIN TUMOR DONATIONS: GIFT FROM A CHILD
Authors: Nicole Lyons, Angela Waanders, Melissa Williams, Javad Nazarian, Augustine Eze, Miriam Bornhorst, Elizabeth Frenkel, Jennifer Mason, Jane E Minturn, Mateusz Koptyra, Michelle Monje, Jared Hysinger, Mark Souweidane, Jeffery P Greenfield, Cindy Campbell, Esteban Uceda, Amy Smith, Julia Hegert, Stephani Campion, Ginny McLean, Patti Gustafson, Allen Gustafson
Journal: Neuro-Oncology (2022)

Abstract Implementation of access to donate post mortem tissue among pediatric brain tumor patients remains a challenge[DSM1] . Previous attempts to develop a post-mortem network have been jeopardized by barriers such as a lack of education, logistical coordination of donation, and difficulties effectively communicating the benefit of post-mortem donations to families. [CC2] Utilizing feedback from patients’ families, clinicians, and researchers, standard operating procedures (SOP) were developed and utilized by six “tissue navigators” (TN) working across institutions. Tissue navigators are critical in implementation of access to donate as they serve as a liaison between patients’ families and clinical team to ensure post-mortem tissue is procured correctly and respectfully. From 2018 through 2021, there has been an increase in donations, which has led to establishment of tumor cell cultures translating rapidly to clinical development, and a growing network of centers participating in GFAC procedures. Donations have been facilitated at over 75 institutions. GFAC has coordinated 146 donations in this 3-year launch timeframe, with nearly half from families outside GFAC’s primary institutional network. Barriers to implementation were addressed with the design of GFAC’s SOPs, which lead to the successful implementation of access to donation. GFAC is developing CME training for clinicians and researchers to address communication of post-mortem donation, continuing awareness campaigns with collaborators in the field, advocating for families to receive feedback on the donation, and expanding on the SOPs as more is learned from clinicians and families.
NCOG-42. THE IMPACT OF PER2 POLYMORPHISMS ON THE EXPRESSION OF SLEEP AND ACTIVITY IN A NOVEL MOUSE MODEL OF CRANIAL-IRRADIATION-INDUCED HYPERSOMNOLENCE (C-RIH)
Authors: Kendra Adegbesan, Francesco Tomassoni Ardori, Sudhirkumar Yanpallewar, Nicole Briceno, Amanda King, Lino Tessarollo, Mark Gilbert, DeeDee Smart, Terri Armstrong, Dorela Shuboni-Mulligan
Journal: Neuro-Oncology (2022)

Abstract Chronic daytime sleepiness, or hypersomnolence, is one of the most common and disruptive side effects of cranial radiotherapy and is associated with disturbances in mood and cognition in primary brain tumor patients. Our laboratory previously found that increased minor allele presence of the PERIOD2 (PER2) polymorphism (rs934945, G-E mutation) correlated with a decreased likelihood of hypersomnolence in PBT patients. PER2, a key molecular component of the circadian clock, assists in the generation and maintenance of daily sleep/wake rhythms. We aim to understand the effects of this PER2 polymorphism on radiation sensitivity within our previously established mouse model of cranial-irradiation-induced hypersomnolence (C-RIH). Five cohorts of male/female transgenic mice were generated using CRISPR-Cas9, replacing the endogenous mouse CRY binding domain with one of two polymorphic variants within the human genome (G-E and conventional Per2h23). General activity and sleep were monitored continuously over 10 days before and after therapeutic irradiation (whole brain, 15Gy, single fraction). Independent samples t-tests compared knock-in groups and species variants. During the active phase, G-E knock-in mice showed less radiation-induced suppression of activity (-7% males; -20% females) relative to Per2h23 knock-ins (-18% males; -36% females). For rest, both male and female G-E mice (+4% males; +16.4% females) expressed less radiation induced sleep during their active phase than Per2h23 mice (+7% males; +27.7% females). However, this pattern did not rise to significance. Current experiments will expand the numbers of mice used in each group to further explore these initial patterns. Understanding the genetic markers that predict radiation sensitivity could help generate more patient specific methods to mitigate these negative behavioral outcomes. Our mouse models provide a platform to introduce polymorphisms and test their impact on treatment-related symptoms.
SURG-04. CDK2NA/B, SMAD4, AND PIK3R1 MUTATIONS ARE ASSOCIATED WITH INCREASED RISK OF LOCAL RECURRENCE AFTER SURGICAL RESECTION OF BRAIN METASTASES
Authors: Ramin A Morshed, Daniel Cummins, Minh Nguyen, Jacob S Young, Philip Theodospoulos, Shawn L Hervey-Jumper, Manish Aghi, Mariza Daras
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND While resection of brain metastases (BMs) offers favorable local disease control, factors and genetic alterations associated with local recurrence are not well defined. This study examined patient, tumor, treatment, and genetic factors associated with local recurrence. METHODS A retrospective, single-center study was conducted with patients who underwent resection of a BM with available clinical outcome and genetic data available. Local recurrence was the primary outcome of the study. Next-generation sequencing of coding regions in over 500 cancer genes was performed to detect mutations. Cox proportional hazards analysis was performed to identify patient, tumor, treatment, and genetic factors associated with local recurrence. RESULTS We identified 91 patients who underwent surgical resection of a BM with available data, of which 80 (87.1%) underwent preoperative radiotherapy or received some form of adjuvant radiation to the resection cavity. Primary pathologies in the cohort included non-small cell lung cancer (24.2%), melanoma (24.2%), breast cancer (16.5%), gastrointestinal cancers (13.2%), gynecologic cancers (4.4%), renal cell carcinoma (4.4%), and other cancers (13.2%). Eleven patients (12.1%) developed postoperative recurrence at the surgical site with 6- and 12-month PFS of 91.2% and 84.2%. Multivariate Cox proportional hazard analysis identified cancer type (Gyn and RCC vs Others: OR 39.4, p=0.002), CDK2NA/B co-deletion (OR 37.52, p=0.0009), PIK3R1 mutation (OR 56.88, p=0.003), and SMAD4 mutation (OR 134.8, p=0.0007) to be associated with time to local recurrence. Overall survival and length of follow-up were not different based on mutational status of these genes, demonstrating that results were not due to survival bias. CONCLUSIONS Genetic alterations within BMs impact clinical outcomes after surgical resection. Further work is needed to determine if targeted therapies for BMs with these alterations can decrease rates of local recurrence.
NIMG-02. PACS-INTEGRATED AUTO-SEGMENTATION WORKFLOW FOR BRAIN METASTASES USING NNU-NET
Authors: Leon Jekel, Khaled Bousabarah, MingDe Lin, Sara Merkaj, Manpreet Kaur, Arman Avesta, Sanjay Aneja, Antonio Omuro, Veronica Chiang, Björn Scheffler, Mariam Aboian
Journal: Neuro-Oncology (2022)

Abstract PURPOSE Monitoring metastatic disease to the brain is laborious and time-consuming, especially in the setting of multiple metastases and when performed manually. Response assessment in brain metastases based on maximal unidimensional diameter as per the RANO-BM guideline is commonly performed1, however, accurate volumetric lesion estimates can be crucial for clinical decision-making2 and enhance outcome prediction3. We propose a deep learning (DL)-based auto-segmentation approach with the potential for improvement of time-efficiency, reproducibility and robustness against inter-rater variability. Materials and METHODS We retrospectively retrieved 259 patients with a total number of 916 lesions from our institutional database from 2014 - 2021. Patients with prior history of local radiation therapy or surgery were excluded. Manually generated trainee segmentations were revised and adjusted by a board-certified radiologist and served as ground truth for evaluation of segmentation accuracy. Model performance was tested via dice-similarity-coefficient (DSC). Volumetric measurements were then obtained within our PACS-integrated workflow on Visage 7 (Visage Imaging, Inc., San Diego, CA) at the click of one button. RESULTS For model training and evaluation, a train-test split of 90:10 on patient-level was performed (n= 234:25 (Patients), n= 861:55 (Lesions). A DL-algorithm (nnUNet) was incrementally trained on 10 batches of 23 patients. The DSC of the U-Net gradually increased throughout the training process and heuristically reached a plateau of 0.85. The sensitivity of the algorithm was 83% with detection of 46 out of 55 lesions in the testing dataset. The lesions that were not detected by the algorithm were below 5 mm in size. The false positive rate was 8% (n=4/50). CONCLUSION Our study demonstrates the feasibility of PACS-based integration of automatized segmentation workflows of brain metastases. An incremental-training approach is recommended to adapt DL algorithms to specific hospital settings.
RBIO-03. A MULTI-INSTITUTIONAL EXPERIENCE OF GAMMATILE BRACHYTHERAPY AS TREATMENT FOR RECURRENT GLIOBLASTOMAS
Authors: Clark Chen, Clara Ferreira, Kathryn Dusenbery, Kimberly Hoang, Stuart Lee, Kris Smith
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Recurrent glioblastoma remains a disease without established standard of care. Here, we report the safety profile and survival outcome of recurrent glioblastoma patients treated with maximal safe resection followed by intraoperative placement of GammaTile (GT), a collagen tile-embedded Cs-131 brachytherapy platform. METHODS The study included isocitrate Dehydrogenase (IDH) wild-type glioblastoma patients who suffered tissue confirmed recurrence after concurrent temozolomide-radiation therapy. The series included consecutively patients treated at the University of Minnesota, Barrow Neurological Institute, Vidant Health, and Emory University Hospital. Survival results were stratified by methyl-guanine methyl transferase (MGMT) promoter methylation status RESULTS In total 48 patients were treated between 2019 and 2022 in this multi-institutional experience. The median days of hospitalization following the procedure was two (range: 1-15), with 72.5% of the GT implanted patients discharged home before postoperative day three. In terms of post-operative course, two patients suffered new-onset seizure post-surgery (4.0%). There was one (2%) 30-day mortality from intracranial hemorrhage secondary to heparinization for an ischemic limb. There were 13% readmission within 30 days, including hydrocephalus (n=2), urinary tract infection (n=1), deep venous thrombosis (n=1), failure to thrive (n=1), and infected wound (n=1). Of note, the patient with the infected wound had suffered a previous wound infection prior to the GT implantation and the pathogenic organism for both infections were the same (S. aureus). With a median follow-up of 250 days, twelve-month local control was 82%. Median overall survival (OS) from the time of diagnosis was 19 and 33 months for the MGMT unmethylated and methylated tumors, respectively. Select patients (n = 6) treated with adjuvant ketogenic diet in addition to GT and subsequent chemotherapy exhibited survival beyond expectation (&amp;gt; 14 mo, median survival not reached). CONCLUSION This multi-institutional experience supports further investigation of GT brachytherapy as a treatment for recurrent glioblastomas.
DDDR-38. A LENTIVIRAL CRISPR SCREEN FOR EPIGENETIC MODULATORS OF CAR T CELL-TARGETED ANTIGENS IN GLIOBLASTOMA CELL LINES
Authors: T Jordan Walter, Nagi Ayad
Journal: Neuro-Oncology (2022)

Abstract Glioblastoma is the most common malignant brain tumor. Unfortunately, outcomes for this cancer are poor. Even with standard of care treatment, the median survival time is only 15 months and the disease is almost universally lethal. Therefore, more effective therapies are urgently needed to treat this condition. One promising treatment is chimeric antigen receptor (CAR) T cell therapy. CAR T cells are white blood cells that are engineered to kill cancer cells expressing certain antigens; however, the potential of this treatment has yet to be fully realized and further work is required for it to be more effective. One strategy for augmenting CAR T cell therapy would be to increase the expression of the targeted antigens on cancer cells. This could be done using small molecule inhibitors of epigenetic pathways that regulate expression of these antigens. Therefore, the goal of this study was to screen for epigenetic genes that regulate expression of antigens currently being targeted in CAR T cell clinical trials for glioblastoma. Using a CRISPR/Cas9 lentiviral vector library, we knocked out various genes encoding epigenetic proteins in human glioblastoma cell lines. Flow cytometry was used to sort for cells with the highest levels of target surface antigen expression. Genomic DNA was isolated from the cells with the highest surface expression of the antigens of interest. The isolated DNA was sequenced to identify the genetic manipulations responsible for increased antigen expression. Future studies will use small molecule inhibitors of the identified epigenetic modulators to augment CAR T cell therapy in mice.
EPID-17. CENTRAL NEUROCYTOMA: RESEARCH TRENDS, MOST CITED PAPERS, AND SCIENTOMETRICS ANALYSIS TO DATE
Authors: Sulaman Durrani, Mohammad Aadil Qamar, Sameer Saleem Tebha, Karim Nathani, Mohamad Bydon
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION Central neurocytoma is the most common primary intra-ventricular tumor in adults being classified by the World Health Organization (WHO) as a benign grade II tumor with a good prognosis. Given the recent advances with regards to this tumor, a bibliometric analysis was due to study the change in research interest and patterns to identify the future direction of research for neurocytomas. MATERIALS AND METHODS A comprehensive Elsevier’s Scopus database search was performed to capture all published and indexed studies to date using the keywords "neurocytoma" and "central neurocytoma". A discrete set of validated bibliometric parameters were extracted and analyzed. All statistical analyses were performed on R 4.1.2. RESULTS A total of 1,002 documents were included in our analysis covering a period between 1910-2021 (111 years). Around 98.5% of the documents were multi-author publications with a collaboration index (CI) of 4.21. Acta Neuropathologica, The American Journal of Surgical Pathology, and Cancer were the journals to include the most number of top ten cited articles (2 out of 10 most cited articles, 20%). Switzerland (4 out of 10, 40%) accounted for the country to have the most number of top 10 most cited articles. The United States of America (5588 out of 16395 citations, 34.1%) had the most number of citations. Lastly, our analysis reported an annual growth rate of 6.9% for the number of papers produced by year. CONCLUSION This is the first bibliometric analysis to study the top 10 most cited articles with regard to neurocytomas. A shift from histopathologic and clinical symptoms toward treatment and management of the tumor was observed in our analysis. These findings highlight the need for investigation into treatment modalities for future research.
DDEL-04. BIOMATERIAL SCAFFOLDS FOR THE DELIVERY OF NEURAL STEM CELL THERAPIES INTO THE GLIOBLASTOMA RESECTION CAVITY
Authors: Hunter Bomba, Lauren Kass, Abigail Carey-Ewend, Kevin Sheets, Alain Valdivia, Morgan Goetz, Ingrid Findlay, Alison Mercer-Smith, Simon Khagi, Shawn Hingtgen
Journal: Neuro-Oncology (2022)

Abstract Therapeutic neural stem cells (tNSCs) are a promising new platform for the treatment of glioblastoma (GBM). tNSCs exhibit a characteristic known as tumor tropism, in which they can migrate towards distant GBM foci via cytokine signaling. Complementarily, genetic engineering of NSCs may be performed to turn the cells into drug-producing therapeutics. Together, this results in NSCs that act as targeted drug delivery vehicles that can seek out and kill invasive GBM lesions post-resection. However, one limitation of this cell therapy platform is that tNSCs delivered directly into the GBM resection cavity are rapidly cleared. We hypothesized that the commercially available, FDA-approved hemostat FLOSEAL® may be used as a drug delivery system for improving cell persistence in the brain, thus resulting in improved therapeutic efficacy. It was found that tNSCs encapsulated in FLOSEAL® were detectable in the brain for over 95 days in mice, a drastic improvement compared to directly injected cells and cells encapsulated in other existing hemostat systems, which persisted 2 weeks or less. However, two in vivo efficacy studies of tNSCs encapsulated in FLOSEAL® yielded contrasting results. While the FLOSEAL®-tNSC system was significantly more efficacious against a GBM8 tumor model in mice compared to directly injected tNSCs, it was not significantly more effective against a U87 tumor model. This could be due to a variety of factors, including the tumor type (diffuse vs. solid for GBM8 and U87, respectively) and negative impacts of FLOSEAL® on tNSC markers of proliferation, migration, drug production, and anti-apoptosis. While FLOSEAL® is a promising material for the delivery of tNSCs in the treatment of post-operative GBM, alternative systems that allow for improved persistence while maintaining the therapeutic activity of the cells would be optimal for long-term treatment with tNSCs.
BIOM-63. IDENTIFICATION OF MIRNA IN CEREBROSPINAL FLUID AND PLASMA AS A BIOMARKER TO SUPPORT MRI EVALUATION AND MONITORING OF PEDIATRIC BRAIN TUMORS
Authors: Anne Coyle, Ariana Familiar, Chao Zhao, Komal Rathi, Madison Hollawell, Namrata Choudhari, Jessica Foster, Ammar Naqvi, Sina Bagheri, Hannah Anderson, Lorenna Vidal, Arastoo Vossough, Philip B Storm, Peter Madsen, Adam C Resnick, Ali Nabavizadeh, Mateusz Koptyra
Journal: Neuro-Oncology (2022)

Abstract MRI is the current gold standard imaging technique for diagnostic evaluation and monitoring of pediatric CNS tumors, however MRI measures are unable to fully relate to tumor biology and molecular stratification. Circulating in blood and cerebrospinal fluid (CSF), miRNAs are an abundant and stable nucleic acid which can be utilized as a tumor biomarker. Relating miRNA biomarkers and radiological tumor measurements may provide improved diagnostic and monitoring tools for pediatric brain tumors. Using a cohort of 54 pediatric brain tumors including low grade glioma, ependymoma, germ cell tumor, medulloblastoma, atypical teratoid rhabdoid tumor and high-grade glioma we attempted to combine MRI findings and circulating miRNA data. The miRNA expression was profiled in 33 CSF and 52 plasma samples using the HTG EdgeSeq platform. Clinically acquired, multi-parametric MRI scans at time-points close in proximity to liquid biopsy collection were collected retrospectively and used to generate volumetric tumor segmentations. We identified unique miRNA targets significantly correlated with MRI features, clinical findings, and patient outcomes. In both CSF and plasma, miRNA expression was identified to correlate with diagnosis and clinical features including tumor grade and survival status (p &amp;lt; 0.05). In CSF, miRNA expression was correlated with MRI measurements including cystic core volume, non-enhancing tumor volume, leptomeningeal disease, tumor size and location (p &amp;lt; 0.05). Combination of miRNA targets and radiomic tumor measurements improved diagnostic predictions between low- and high-grade tumors. In plasma, miRNA expression was correlated with MRI measurements including cystic core volume, location, and leptomeningeal disease (p &amp;lt; 0.05). These results demonstrate utility of miRNAs as a pediatric brain tumor biomarker which combined with imaging features can improve minimally to non-invasive diagnostics and management of pediatric brain tumors.
RADT-10. THE LOST METASTASES: DEEP LEARNING’S POTENTIAL IN RADIOSURGERY QUALITY ASSURANCE
Authors: Charmin Bang, Gabriel Chartrand, Sophie Pawlowski, Ramon Emiliani, Daniel Markel, Houda Bahig, Alexandre Samak, Selvan Rajakesari, Jérémi Lavoie, Simon Ducharme, David Roberge
Journal: Neuro-Oncology (2022)

Abstract Introduction Identifying, segmenting, measuring, and following multiple brain metastases treated with radiosurgery can be time consuming and error prone. Machine learning has shown promise for automated detection and segmentation. Recently, a U-Net inspired model combining volume aware loss functions and volume aware sampling methods was trained in an industrial-academic partnership. A total of 530 clinically annotated T1 gadolinium MRIs were used. Initial validation showed a high sensitivity (91%) with an average of 0.66 false positives per MRI. The goal of the present work was to characterize those “false positives” which may represent clinically undetected metastases. METHODS The images used for model development were clinically annotated for radiosurgery planning. Lesions had first been identified by a radiologist, second by clinicians during tumor board review, third by the treating radiation oncologist and the treating neurosurgeon (potentially after segmentation by a trainee) and finally by fellow radiation oncologists during quality assurance rounds. Despite these multiple checks, 10 patients (2%) had brain lesions considered potential clinical misses when all “false positives” were manually reviewed by a single investigator. Further detailed review including prior and subsequent imaging was used to arbitrate the nature of these lesions. RESULTS Among the 10 cases, four were confirmed as undetected metastases: two lesions required subsequent radiosurgery and 2 patients died prior to further imaging. The six other lesions were adjudicated as true “false positives” (typically vascular). CONCLUSION The multi-tier radiosurgery workflow at our institution left very few unidentified brain metastases (0.8%). Despite this low error rate, our AI algorithm still detected two lesions that required further treatment. Future investigations will focus on potential roles of AI in simplifying and accelerating our workflow. It also remains to be established if more undetected metastases would be seen in community settings where workflows include fewer sequential imaging reviews.
TMIC-50. AN INNOVATIVE THREE-DIMENSIONAL GELATIN FOAM CULTURE SYSTEM FOR IMPROVED STUDY OF GLIOBLASTOMA STEM CELL BEHAVIOR
Authors: Meng-Yin Yang, Chun-Pi Chang
Journal: Neuro-Oncology (2022)

Abstract Three-dimensional (3-D) tissue engineered constructs provide a platform for examining how the local extracellular matrix contributes to the malignancy of various cancers, including human glioblastoma multiforme. Here, we describe a simple and innovative 3-D culture environment and assess its potential for use with glioblastoma stem cells (GSCs) to examine the diversification inside the cell mass in the 3-D culture system. The dissociated human GSCs were cultured using gelatin foam. These cells were subsequently identified by immunohistochemical staining, reverse transcriptase-polymerase chain reaction, and Western blot assay. We demonstrate that the gelatin foam provides a suitable microenvironment, as a 3-D culture system, for GSCs to maintain their stemness. The gelatin foam culture system contributes a simplified assessment of cell blocks for immunohistochemistry assay. We show that the significant transcription activity of hypoxia and the protein expression of inflammatory responses are detected at the inside of the cell mass in vitro, while robust expression of PROM1/CD133 and hypoxia-induced factor-1 alpha are detected at the xenografted tumor in vivo. We also examine the common clinical trials under this culture platform and characterized a significant difference of drug resistance. The 3-D gelatin foam culture system can provide a more realistic microenvironmentthrough which to study the in vivo behavior of GSCs to evaluate the role that biophysical factors play in the hypoxia, inflammatory responses and subsequent drug resistance.